Nagel-Wolfrum Kerstin, Möller Fabian, Penner Inessa, Wolfrum Uwe
Department of Cell and Matrix Biology,Institute of Zoology,Johannes Gutenberg-University of Mainz,Mainz,Germany.
Vis Neurosci. 2014 Sep;31(4-5):309-16. doi: 10.1017/S0952523814000194. Epub 2014 Jun 10.
The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.
眼睛已成为基因治疗的一个理想靶点，近年来遗传性视网膜疾病的基因增强疗法取得了重大进展。然而，最近一项研究表明，基因增强干预可能无法阻止患者视网膜变性的进展。此外，对于许多基因来说，由于基因大小、病毒载体的包装能力有限以及靶基因各种异质异构体的表达，目前病毒介导的基因增强是不可行的。因此，需要采取基于基因的替代策略来阻止或延缓视网膜变性。本综述重点介绍了一种基于使用翻译通读诱导药物（TRIDs）的替代药物治疗策略，如PTC124、氨基糖苷类抗生素和设计氨基糖苷类药物，用于通读框内无义突变。这种策略已成为所有隐性遗传性视网膜营养不良病例中高达30-50%的一种选择。框内无义突变是基因编码序列内的单核苷酸改变，导致过早的终止密码子。因此，这种突变基因的翻译导致截短蛋白的合成，而截短蛋白无法发挥其生理功能。在这种情况下，应用TRIDs有助于将过早终止密码子重新编码为有义密码子，从而恢复全长蛋白的合成。到目前为止，已经针对多种TRIDs启动了非眼部疾病的临床试验。虽然没有详细分析临床结果，但已清楚证明了其良好的安全性，即对于PTC124而言。此外，最近的数据表明，导致视网膜变性的无义突变具有持续的通读效率，如在人类Usher综合征中所示。此外，已证明PTC124和设计氨基糖苷类药物具有很强的视网膜生物相容性。总之，最近的进展强调了TRIDs作为治疗基于无义突变的视网膜疾病的替代药物治疗策略的潜力。
